Ventilatory assistance for treatment of cardiac failure and cheyne-stokes breathing

ABSTRACT

Method and apparatus for the treatment of cardiac failure, Cheyne Stokes breathing or central sleep apnea are disclosed. A subject is provided with ventilatory support. Respiratory airflow is determined. From the respiratory airflow are derived a measure of instantaneous ventilation (for example half the absolute value of the respiratory airflow) and a measure of longterm average ventilation. A target ventilation is taken as 95% of the longterm average ventilation. The instantaneous ventilation is fed as the input signal to a clipped integral controller, with the target ventilation as the reference signal. The output of the controller determines the degree of ventilatory support. A third measure of ventilation, for example instantaneous ventilation low pass filtered with a time constant of 5 seconds, is calculated. Ventilatory support is in phase with the subject&#39;s respiratory airflow to the fuzzy extent that this ventilation is above target, and at a preset rate conversely.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 13/962,493, filed Aug. 8, 2013 which is a continuation of U.S.patent application Ser. No. 13/114,884, filed May 24, 2011, now U.S.Pat. No. 8,528,556 which is a continuation of U.S. patent applicationSer. No. 11/457,564 filed Jul. 14, 2006, now U.S. Pat. No. 7,967,012,which is a continuation of U.S. patent application Ser. No. 10/865,944filed Jun. 11, 2004, now U.S. Pat. No. 7,077,132, which is acontinuation of U.S. patent application Ser. No. 10/374,487 filed Feb.26, 2003, now U.S. Pat. No. 6,951,217, which is a continuation of U.S.patent application Ser. No. 09/316,432 filed May 21, 1999, now U.S. Pat.No. 6,532,959, which claims priority from Australia PP3663 filed May 22,1998, the disclosure of which is hereby incorporated herein byreference.

FIELD OF THE INVENTION

The invention relates to methods and apparatus for the provision ofpositive pressure ventilatory assistance for patients with cardiacfailure or Cheyne-Stokes breathing from any cause, including centralsleep apnea, cardiac failure or stroke.

EXPLANATION OF TERMS

In this specification, respiratory airflow is intended to refer to theinstantaneous flow of gas into or out of the lungs. The term “average”is intended to mean any measure of central tendency or the result of anylow pass filtering operation. Ventilatory support is intended to meanany procedure which has a similar effect as the respiratory muscles,particularly the supply of breathable gas under varying positivepressure to the airway via a nosemask, face mask, endotracheal tube,tracheotomy tube, or the like, but also including other procedures suchas negative pressure ventilation, cuirasse, iron lung, external chestcompression, or rocking bed ventilation. According to common usage,ventilation can mean either a procedure, as in the expression “positivepressure ventilation”, or a measure of average respiratory airflow overa period of time. Instantaneous ventilation is intended to mean thevolume inspired over a short period of time less than several seconds.Equally it can be calculated as the volume expired over such a period,or it can be the average of the two. For example, measures ofinstantaneous ventilation would include half the average of the absolutevalue of the respiratory airflow, calculated over a time interval shortcompared with several seconds, or half the absolute value of therespiratory airflow, low pass filtered with a time constant shortcompared with several seconds. For technical reasons to be explainedbelow, in the best embodiment, instantaneous ventilation is taken ashalf the absolute value of the instantaneous respiratory airflow, ieaveraged over an arbitrarily short period of time. However, it is notintended that the invention is limited to calculating instantaneousventilation in this way.

The term “varying A inversely with B” is intended in the broad sense ofincreasing A if B is decreasing, and decreasing A if B is increasing.

The term “servo-controller” here refers to a feedback controlleraccepting an input, or controlled, variable (for example actual measuredventilation) and a reference quantity (for example a desired or targetventilation), and producing an output (for example the settings of aventilator) which is used to subsequently bring the value of the input(controlled) variable towards the value of the reference variable.

The term “oppose” can include reduce, limit, dampen, or prevent.

The terms “recent average ventilation” and “longterm averageventilation” are to be understood to be equivalents.

BACKGROUND OF THE INVENTION

Patients with cardiac failure have reduced cardiac ejection fraction,are typically very breathless, and often wake at night with extremebreathlessness called paroxysmal nocturnal dyspnea, due to accumulationof fluid in the lungs.

Patients with cardiac failure also often have Cheyne-Stokes breathing,particularly during sleep. Cheyne-Stokes breathing is an abnormal limitcycle instability of the patient's respiratory controller in which thereare rhythmic alternating periods of waxing and waning ventilation,causing repetitive deoxygenation and reoxygenation of the arterialblood. The cause of the waxing and waning of ventilation is not entirelyclear, but there is an increase in chemoreceptor gain [Wilcox I et al.Ventilatory control in patients with sleep apnoea and left ventriculardysfunction: comparison of obstructive and central sleep apnoea. 1998;11:7-13], possibly related to stimuli arising in the heart or lungs, achange in the chemoreceptor set point leading to overventilation andalkalosis in the awake state with apneas during sleep, and an increasein circulation time leading to delays between ventilation andchemoreception [Naughton M et al. Role of hyperventilation in thepathogenesis of central sleep apneas in patients with congestive heartfailure. Am Rev Respir Dis 1993; 148:330-338]. Cheyne-Stokes breathingis associated with high mortality [Andreas et al. Cheyne-Stokesrespiration and prognosis in congestive heart failure. Am J Cardiol1996; 78:1260-1264]. It is possible that it is harmful because of therepetitive hypoxia, which will lead to hypoxic pulmonaryvasoconstriction and high right heart afterload, and to increasedsympathetic activity, systemic vasoconstriction and high left heartafterload. It may also be harmful because of repetitive alkalosis duringthe waxing period of the cycle. Finally, in some patients it isassociated with repetitive arousal from sleep, which causes severe sleepdisruption, increased sympathetic activity, and increased afterload.

Continuous positive airway pressure (CPAP) has been used for decades forthe emergency treatment of pulmonary oedema, and is more recently beingused longterm during sleep for the treatment of cardiac failure. NasalCPAP leads to an improvement in cardiac output and ejection fraction,and an improvement in quality of life [Naughton M T et al, Treatment ofcongestive heart failure and Cheyne-Stokes respiration during sleep bycontinuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92-97], and a reduction in sympathetic nervous system activity[Naughton M T et al, Effects of nasal CPAP on sympathetic activity inpatients with heart failure and central sleep apnea Am J Respir GritCare Med 1995; 152:473-479]. The precise mechanism of action is unclear.Making the alveolar pressure and right atrial pressure positive withrespect to the inferior vena caval pressure, and making the leftventricular pressure more positive with respect to abdominal aorticpressure, will tend to dry the lungs, improve gas exchange, relieveparoxysmal nocturnal dyspnea, reduce reflex pulmonary vasoconstriction,reduce sympathetic activity and reduce cardiac afterload via multiplecomplex mechanisms. Standard nasal CPAP masks may also help stabilizeCheyne-Stokes breathing, because the effective ventilation cannot exceedthe fresh gas flow, which is in turn set by the exhaust flow. Finally,many patients with cardiac failure also have coexisting obstructivesleep apnea, which worsens cardiac failure but is treated by nasal CPAP.

Unfortunately, despite excellent effectiveness, nasal CPAP is oftenpoorly tolerated by patients with cardiac failure, particularly early onin treatment, and it has not become widely used. The reasons for thepoor tolerance are unknown. In addition, nasal CPAP reduces, butunfortunately does not immediately suppress the Cheyne-Stokes breathing[Naughton M T et al. Effect of continuous positive airway pressure oncentral sleep apnea and nocturnal PCO2 in heart failure. Am J RespirCrit Care Med 1994; 150:1598-1604].

Various other approaches using known methods of ventilatory assistancesuggest themselves in order to provide the same benefit as CPAP whilealso reducing either respiratory work or Cheyne-Stokes breathing orboth. Unfortunately no known device is completely satisfactory, eitherbecause of discomfort, overventilation, or both. For example, FIG. 1shows persistent Cheyne-Stokes breathing in a patient with cardiacfailure being treated with bilevel ventilatory support with timedbackup. The subject is in stage 3 non-REM sleep. The polygraph tracingsare arterial haemoglobin oxygen saturation (top tracing), chest wallmovement (middle tracing), and mask pressure (bottom tracing). TheCheyne-Stokes breathing persists. Note, in the middle trace, thecyclical waxing and waning of the amplitude of chest wall movement,indicating periods of overbreathing and underbreathing, and resultantregular decreases in arterial haemoglobin oxygen saturation despite theventilatory support.

Many classes of ventilator, far from increasing comfort, actuallydecrease comfort. Volume cycled ventilators (regardless of the triggervariable) and time triggered ventilators (regardless of the cyclingvariable) often show very poor synchronization between machine andpatient, which is distressing to the patient. Volume cycled ventilatorsand high impedance pressure cycled ventilators do not permit the patientto increase or decrease ventilation voluntarily, which is alsodistressing to the patient. Subjects with Cheyne-Stokes breathing may beparticularly distressed by inadequate volume settings, due to their highchemoreceptor gain.

Another serious problem is overventilation. Most ventilatory assistancedevices are designed to replace or augment respiratory effort insubjects with respiratory failure or insufficiency, and by design, causea net increase in mean ventilation above the subject's spontaneous meanventilation. Unfortunately, in subjects who are not initially acidotic,such as the subjects of the present discussion, ventilatory assistancecauses or exacerbates hypocapnia and alkalosis, leading in turn toreflex upper airway and particularly vocal cord closure during sleep[Jounieux et al. Effects of nasal positive pressure hyperventilation onthe glottis in normal sleeping subjects. J Appl Physiol 1995;79:186-193]. Far from treating the disordered breathing, excessiveventilatory support will actually produce closed airway central apneas.Some ventilatory assistance devices, in an attempt to provide increasedcomfort, support ventilation specifically during periods of increasedpatient effort (for example proportional assist ventilation and allclasses of ventilators with spontaneous triggering without timedbackup). This will yet further enhance any tendency to cyclicallydisordered breathing during sleep. Similarly, in the case of volumecycled ventilators, awake comfort can usually only be achieved byoverventilation, with alkalosis and consequent airway closure in sleep.Overventilation and alkalosis can sometimes be extremely dangerous.Indeed, in patients with cardiac failure and acute pulmonary edema,bilevel ventilation with fixed high pressure swings appears to beassociated with an increased risk of myocardial infarction [Mehta et al.Randomized prospective trial of brevet versus continuous positive airwaypressure in acute pulmonary oedema. Crit Care Med 1997; 25:620-628].

Another approach to the overventilation problem is to provideventilatory assistance only during periods of reduced subject efforts,for example by triggering the ventilator only if the subject has notproduced an inspiration for at least a specified period of time. This isunsatisfactory for three reasons. Firstly, during spontaneous breathing,this solution will not provide any increase in comfort over normal CPAP,and this was one of the problems to be solved. Secondly, the suddenabrupt increase in support at the onset of an apnea will in general tendto awaken the patient from sleep, leading to both sleep fragmentationand transient overventilation leading to further sleep disorderedbreathing. Thirdly, as with all previous methods, it is difficult to setthe level of support during periods of central apnea high enough toprevent Cheyne-Stokes breathing or central sleep apneas, but not so highas to produce airway closure.

A more satisfactory approach is described in commonly ownedInternational Publication No. WO 98/12965, in which a target ventilationis selected, and the degree of support is automatically adjusted toservo-control the measured ventilation to at least equal the targetventilation. A minimum level of support, chosen not to produceoverventilation, is provided for comfort during awake breathing. If thetarget ventilation is chosen to be slightly less than the eupneicventilation, then Cheyne-Stokes breathing and central sleep apnea may beprevented without the risk of overventilation. Because the degree ofsupport increases smoothly as the subject's own efforts decrease, thereis no explosively sudden increase in support which might wake thepatient. However, there are two limitations to having a fixed targetventilation. Firstly, the target ventilation needs to be chosen, andthis can be difficult: too high a value will lead to overventilation,while too low a value will permit some residual Cheyne-Stokes breathing.Secondly, due to changes in metabolic rate with restlessness, sleepstate, body temperature, meals, etc, the ideal target ventilation is notconstant.

In summary, longterm nasal CPAP therapy is of known benefit in thetreatment of cardiac failure, but is poorly tolerated, and does notusually or completely alleviate Cheyne-Stokes breathing or central sleepapnea, at least initially. Attempting to increase tolerance and/or treatthe disordered breathing using ventilatory support is difficult, or onlypartially successful, depending on the device used, because of the needto avoid overventilation. Very similar comments apply to the treatmentof Cheyne-Stokes breathing and/or central sleep apnea due to many othercauses in such as stroke or acromegaly.

DISCLOSURE OF THE INVENTION

The present invention is directed to providing a subject with cardiacfailure positive airway pressure therapy, to achieve an improvement inthe symptoms and signs of cardiac failure similar to that afforded byCPAP, by modulating the mask pressure in such a way as to provideincreased comfort without overventilation, hypocapnia, alkalosis, orupper airway closure. The present invention is further directed to thestabilization or prevention of Cheyne-Stokes breathing or central sleepapnea from many causes.

The invention discloses a method for treatment of cardiac failure,Cheyne-Stokes breathing, or central sleep apnea, comprising the stepsof:

providing a subject with ventilatory support;

deriving a measure of instantaneous ventilation; and

adjusting the degree of ventilatory support to oppose short term changesin said measure of instantaneous ventilation, but permitting longtermchanges in said measure of instantaneous ventilation.

The invention further discloses apparatus for the treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising:

a device for providing ventilatory support of controllable magnitude;

means for deriving a signal indicative of instantaneous ventilation of asubject;

a servo-controller operable to control the degree of ventilatory supportprovided by said ventilatory support device to oppose short-term changesin said measure of instantaneous ventilation, but permit longtermchanges in said measure of instantaneous ventilation.

The invention discloses a method for treatment of cardiac failure,Cheyne-Stokes breathing or central sleep apnea, comprising the steps of:

providing a subject with ventilatory support;

deriving a measure of the subject's instantaneous ventilation; and

adjusting the degree of ventilatory support to reduce changes in saidmeasure of instantaneous ventilation over a timescale similar to that ofthe waxing-waning cycle of untreated Cheyne-Stokes breathing or centralsleep apnea, while allowing changes in said measure of instantaneousventilation over a timescale much longer than said waxing-waning cycle.

The invention further discloses a method for treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising thesteps of:

providing a subject with ventilatory support;

deriving a measure of the subject's instantaneous ventilation;

deriving a measure of the subject's longterm average ventilation;

setting the controlled variable of a servo-controller to a function ofsaid measure of the subject's instantaneous ventilation;

setting the reference variable of said servo-controller to a measure ofthe subject's longterm average ventilation; and

adjusting the magnitude of said ventilatory support in accordance withthe output of said servo-controller.

The invention yet further discloses a method for treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising thesteps of:

providing a subject with ventilatory support;

deriving a measure of the subject's instantaneous ventilation;

high pass filtering said measure of the subject's instantaneousventilation; and

adjusting the degree of said ventilatory support inversely with saidhigh pass filtered measure of the subject's instantaneous ventilation.

The invention also discloses a method for the treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising thesteps of:

providing a subject with positive pressure ventilatory support, withcontrollable amplitude and rate;

deriving a measure of the subject's instantaneous ventilation;

adjusting said amplitude of positive pressure by:

-   -   (a) low pass filtering said measure of instantaneous ventilation        to derive a measure of recent average ventilation;    -   (b) setting a target ventilation equal to a fraction of said        measure of recent average ventilation; and    -   (c) servo-controlling said measure of instantaneous ventilation        to at least equal the target ventilation, by adjusting the        degree of ventilatory support;

continuously adjusting said rate by:

-   -   (a) to the extent that the instantaneous ventilation equals or        exceeds said target ventilation, modulating said positive        pressure in phase with respiratory airflow; and    -   (b) to the extent that the instantaneous ventilation is less        than said target ventilation, modulating said positive pressure        at a pre-set rate.

The invention further discloses apparatus for treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising:

a controllable source of breathable gas at positive pressure;

means for delivering said breathable gas at positive pressure to asubject's airway;

means for deriving a measure of the subject's instantaneous ventilation;and servo-controller for adjusting the degree of ventilatory support toreduce changes in said measure of instantaneous ventilation over atimescale similar to that of the waxing-waning cycle of untreatedCheyne-Stokes breathing or central sleep apnea, while allowing changesin said measure of instantaneous ventilation over a timescale muchlonger than said waxing-waning cycle.

The invention yet further discloses apparatus for treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising:

a controllable source of breathable gas at positive pressure;

means for delivering said breathable gas at positive pressure to asubject's airway;

means for deriving a measure of the subject's instantaneous ventilation;

means for deriving a measure of the subject's longterm averageventilation;

means for deriving a target ventilation as a function of said measure ofthe subject's longterm average ventilation;

a servo-controller, whose input variable is a function of said measureof the subject's instantaneous ventilation, and whose reference variableis said target ventilation; and

means for adjusting the magnitude of said ventilatory support accordingto the output of the servo-controller.

The invention also discloses apparatus for the treatment of cardiacfailure, Cheyne-Stokes breathing or central sleep apnea, comprising:

ventilator means for providing ventilatory support with controllableamplitude and rate;

sensor and processing means for deriving a signal indicative ofinstantaneous ventilation of a subject; and

servo-control means operable to adjust the amplitude of the pressuresupport by low pass filtering said instantaneous ventilation signal toderive a measure of recent average ventilation, setting a targetventilation equal to a fraction of said measure of recent averageventilation, and servo-controlling said measure of instantaneousventilation to at least equal the target ventilation, and furtheroperable to continuously adjust said rate by modulating said positivepressure in phase with respiratory airflow to the extent that theinstantaneous ventilation equals or exceeds said target ventilation, andmodulating said positive pressure at a pre-set rate to the extent thatthe instantaneous ventilation is less than said target ventilation.

Embodiments of the invention provide a degree of ventilatory supportwhich many subjects will perceive as very comfortable. Cheyne-Stokesbreathing is reduced or eliminated. Unlike the case of prior art taughtin International Publication No. WO98/12965, the physician is notrequired to estimate or empirically determine a target ventilation, asthis is done automatically. The risk of overventilating the subject andcausing alkalosis or airway closure is also reduced.

BRIEF DESCRIPTION OF THE DRAWINGS

Embodiments of the present invention will now be described, by way ofexample only, with reference to the accompanying drawings.

FIG. 1 is a plot of a 10 minute excerpt from a polygraph tracing from asleeping patient with cardiac failure, during treatment with prior artbilevel ventilation in Stage Ill non-REM sleep.

FIG. 2 is a schematic diagram of ventilation apparatus embodying theinvention.

FIG. 3 is a plot of a pressure waveform template. The horizontal axis φis the phase in the respiratory cycle, measured in revolutions, suchthat 0 is start of inspiration, 0.5 revolutions is start of expiration,and 1 revolution is end of expiration.

FIG. 4 is a plot of a 10 minute excerpt from a polygraph tracing fromthe subject from FIG. 1, also in Stage III non-REM sleep, being treatedby an embodiment of the present invention. Cheyne-Stokes breathing hasbeen eliminated.

FIG. 5 is a schematic diagram showing respiratory airflow duringCheyne-Stokes breathing, and various calculated quantities, includingtwo measures of “instantaneous” ventilation, “recent average”ventilation, and “target” ventilation with time.

FIG. 6 is a schematic diagram showing, for a preferred embodiment, theexpected increase in degree of ventilatory support in response to asudden cessation of all respiratory efforts by the subject with time.

FIG. 7 is a schematic diagram showing, for the preferred embodiment, howthe degree of assistance will remain at the minimum level if thesubject's ventilation steadily decreases over a very long time period.

DETAILED DESCRIPTION

A ventilator embodying one form of the invention is shown in FIG. 2 inwhich a blower 10 supplies breathable gas to a mask 11 for communicationwith a subject's airway via a delivery tube 12 and exhausting toatmosphere via an exhaust 13. Airflow at the mask 11 is measured using apneumotachograph 14 and a differential pressure transducer 15. The maskflow signal 22 from the transducer 15 is sampled by a microcontroller16. Mask pressure is measured at port 17 using a pressure transducer 18.The pressure signal 24 from the transducer 18 is also sampled by themicrocontroller 16. The microcontroller 16 sends an instantaneous maskpressure request signal 26 to a servo 19, which compares the pressurerequest signal (ie. the desired pressure signal) 26 with the actualpressure signal 24 from the transducer 18 to control a motor 20 drivingthe blower 10. The microcontroller 16 settings can be adjusted via aserial port 21.

It is to be understood that the mask could equally be replaced with atracheotomy tube, endotracheal tube, nasal pillows, or other means ofmaking a sealed connection between the air delivery means and thesubject's airway.

The steps performed by the microcontroller 16 to determine the requestedmask pressure will now be described.

The microcontroller 16 accepts the mask airflow and pressure signals 22,24, and from said signals determines the instantaneous flow through anyleak between the mask and subject, by any convenient method. Forexample, the conductance of the leak may be estimated as theinstantaneous mask airflow low pass filtered with a time constant of 10seconds, divided by the similarly low pass filtered square root of theinstantaneous mask pressure, and the instantaneous leakage flow may becalculated as said conductance multiplied by the square root of theinstantaneous mask pressure. Respiratory airflow is then calculated asthe instantaneous mask airflow minus said instantaneous leakage flow.

Having determined the respiratory airflow, the microcontroller 16 nowdetermines the subject's recent average absolute respiratory airflow asthe 100 second low pass filtered absolute value of the respiratoryairflow. The 100 second time constant is chosen because it is longcompared with the lung-chemoreceptor delay in patients withCheyne-Stokes breathing or central sleep apnea (typically up to 20 sec),and somewhat longer than the cycle time of typical Cheyne-Stokesbreathing of about 60 seconds. Longer time constants will in principlegive better suppression of Cheyne-Stokes breathing as long as thesubject's chemoreceptor set-point is constant, but will take longer tosettle at sleep onset and longer to track changes in set-point. The term“recent average” is used in the sense of recent compared with an entirenight's sleep. However, compared with “instantaneous” ventilation, whichis measured on a timescale of a single breath or less, the 100 secondlow pass filtered absolute value of the respiratory airflow is, ofcourse, a longterm average.

A target absolute respiratory airflow is then calculated as 95% of saidrecent average absolute respiratory airflow. Larger values can result inpositive feedback leading to drift in the ventilation, while smallervalues will permit residual Cheyne-Stokes breathing.

FIG. 5 shows the above steps schematically. The top tracing in thefigure is respiratory airflow. The second tracing, labelled“Instantaneous Ventilation 1”, is the absolute value of the respiratoryairflow. The bottom tracing shows, schematically, another measure ofinstantaneous ventilation, labelled “Instantaneous Ventilation 2”, whichis Instantaneous Ventilation 1 low pass filtered with a time constant ofa few breaths. Instantaneous Ventilation 2, as a measure of ventilation,could equally be schematically the recent average ventilation and thetarget ventilation.

Having calculated the target ventilation, a microcontroller nowcalculates a mask pressure modulation amplitude A. The object of thisstep is to modulate the pressure modulation amplitude in a directionopposite to changes in the output from the subject's own respiratorycontroller, providing more support when the subject is making shallowefforts, and less support when the subject is making strong efforts,thus stabilizing the subject's breathing. It is necessary in this stepthat the servo-controller should have a delay that is very shortcompared with the delay in the subject's own respiratory controller; along delay would further destabilize the subject's breathing. If aproportional or integral controller were fed with a measure of thesubject's ventilation taken over many seconds, for example, longer thanthe case of “Instantaneous Ventilation 2” in FIG. 5, the controllerdelay would be too long. Conversely, if a proportional controller weresupplied with the rectified instantaneous respiratory airflow (as inInstantaneous Ventilation 1 in FIG. 5), then the controller output wouldbe varying out of phase with the subject's breathing efforts, and thesubject would perceive an increase in the work of breathing. In thepresent implementation, a clipped integral controller is fed withInstantaneous Ventilation 1, the absolute value of the respiratoryairflow. The process of integration both smooths and delayswithin-breath changes in the amplitude A, so that the subject does notperceive any increase in work of breathing. A suitable algorithm is asfollows:

-   -   calculate an error term e equal to the instantaneous absolute        respiratory airflow minus the target absolute respiratory        airflow;    -   set the pressure modulation amplitude A equal to

A=f·Gedt

-   -   where G is the controller integral gain, typically −0.3 cmH₂0        L/min per second, and the integral A is clipped to a convenient        range such as 3-12 cmH₂0.

Larger values of G can result in positive feedback in the controller.Smaller values will permit some residual untreated Cheyne-Stokesbreathing or central sleep apnea. The minimum amplitude (3 cmH20 being asuitable value suitable for most subjects) is chosen to be of the orderof 50% of the estimated amplitude required to perform all therespiratory work of the subject in the steady state. A minimum value ofthis order of magnitude provides much improvement in comfort over aminimum value of zero. The maximum amplitude (12 cmH20 being typical) ischosen to be approximately double the amplitude that would perform allthe respiratory work of the subject (and therefore sufficient to supportthe subject's breathing if they cease making any efforts) but less thana value that would be uncomfortable or dangerous.

The microcontroller 16 then determines the instantaneous phase φ in therespiratory cycle from the instantaneous respiratory airflow, looks up apressure waveform template II(φ) and sets the instantaneous maskpressure to:

P _(mask) =P ₀ +AII(φ)

where P_(o) is an end expiratory pressure, typically 5-10 cmH₂O, butchosen to be sufficient to treat any underlying obstructive sleep apneasyndrome.

In a simplest embodiment, the respiratory phase is taken as bivalued:inspiratory if the instantaneous respiratory airflow is positive, andexpiratory otherwise, and II(φ) is unity for inspiration and zero forexpiration. If phase has been expiratory for more than a set time,chosen to be slightly longer than the subject's normal expiratory time,then the phase is switched to inspiratory.

In another embodiment, φ is a continuous variable from zero to 1revolution, and the pressure waveform template II(φ) is as shown in FIG.3. In this embodiment, the microcontroller determines φ using thefollowing fuzzy logic rules:

1. If the airflow is zero and increasing fast then the phase is 0revolutions.

2. If the airflow is large positive and steady then the phase is 0.25revolutions.

3. If the airflow is zero and falling fast then the phase is 0.5revolutions.

4. If the airflow is large negative and steady then the phase is 0.75revolutions.

5. If the airflow is zero and steady and the 5 second low pass filteredabsolute value of the respiratory airflow is large then the phase is 0.9revolutions.

6. If the airflow is positive and the phase is expiratory, then thephase is 0 revolutions.

7. If the airflow is negative and the phase is inspiratory, then thephase is 0.5 revolutions.

8. If the 5 second low pass filtered absolute value of the respiratoryairflow is small, the phase in the respiratory cycle is increasing at afixed rate equal to the subject's expected respiratory rate.

9. If the 5 second low pass filtered absolute value of the respiratoryairflow is large, the phase in the respiratory cycle is increasing at asteady rate equal to the existing rate of change of phase, low passfiltered with a time constant of 20 seconds.

The fuzzy extent to which the airflow is “large”, “steady”, etc can bedetermined with suitable membership functions.

Rules 1-4 estimate the phase directly from the instantaneous respiratoryairflow. Rule 5 permits an expiratory pause, whose length may be long ifthe subject has recently been breathing adequately, and short or zero ifthe subject is not breathing. This is particularly appropriate forsubjects with Cheyne-Stokes breathing, because an expiratory pauseshould not be permitted if the subject is apneic. Rules 6-7 provide forquick resynchronization in the event that the subject breathesirregularly. Rule 8 provides the equivalent of a timed backup, in which,to the extent that the subject has stopped breathing or is notadequately breathing, the ventilator will cycle at a suitable fixedrate. Rule 9 provides that to the extent that the subject is breathingadequately, the ventilator will tend to track the subject's recentaverage respiratory rate. This is particularly appropriate in subjectswith cardiac failure and Cheyne-Stokes breathing, whose respiratory ratetends to be extremely steady despite rhythmic changes in amplitude.

An effect of the changing degree of activation of rules 8 and 9 is that,to the fuzzy extent that the instantaneous ventilation equals or exceedsthe target ventilation, ventilatory support will be provided in phasewith the subject's own respiratory efforts, and to the extent that theinstantaneous ventilation is less than the target ventilation,ventilatory support will be provided at a pre-set rate.

In an elaboration of this embodiment, the weighting of rules 1-6 can bemade proportional to the fuzzy extent that the instantaneous ventilationis large compared with the target ventilation. This strengthens thetendency for the device to act as described in the previous paragraph.

In a further elaboration, the weighting of rules 1-6 and also of rule 9can be made smaller, and the weighting of rule 8 can be larger, if theleak is large, or if there is a sudden change in the leak. In this way,to the extent that the respiratory airflow signal is of high quality,ventilatory support will be provided as described in the precedingparagraphs, but to the extent that the respiratory airflow signal is ofpoor quality and it is difficult to synchronize reliably with thepatient's efforts, or to know if the patient's efforts are adequate,ventilatory support will be provided in an orderly manner at apredetermined fixed rate.

Assuming that the sleeping subject's PC02 is stable at slightly abovethe subject's chemoreceptor set-point and the airway is open, the systemwill remain stable. This is explained as follows. The minimum amplitude,A, of 3 cmH20 will be unloading some of the subject's high work ofbreathing, but is too small to provide all the respiratory work neededto maintain ventilation and PC02 at the subject's set-point. Therefore,there will be an error signal from the subject's chemoreceptors.Therefore the subject will be making spontaneous ventilatory efforts(but less than usual), and the upper airway will be patent. Since thetarget ventilation is only 95% of the spontaneous ventilation, theactual ventilation will be slightly higher than the target ventilation,and the integrator determining amplitude A will remain clipped at theminimum amplitude. If there is a primary reduction in the subject'sventilation of more than 5% due to a primary reduction in ventilatoryeffort or increase in airway resistance, there will be an immediate andrapid increase in the amplitude A by sufficient to maintain ventilationat a level of at least 95% of the previous spontaneous level, thuspreventing hypopneas.

An example is shown schematically in FIG. 6. For the first 4 breaths,the subject is making steady respiratory efforts, and the pressuremodulation amplitude A remains at the minimum value of 3 cmH₂0.Respiratory airflow is due to the combined efforts of subject andventilation apparatus. At the first vertical line, I, the subject'sspontaneous efforts cease. For the next 12 breaths, all respiratoryairflow is due only to the machine. The first breath is deliveredapproximately on schedule, but produces less respiratory airflow thanusual, because only the minimum degree of support is provided. Over thenext few breaths, the amplitude A quickly increases to the maximum of 10cmH₂0, restoring respiratory airflow to almost its original level. Atthe second vertical line, II, the subject recommences spontaneousrespiratory efforts at the previous level, and the degree of machinegenerated support quickly reduces again. It is to be noted in FIG. 6that during a period of cessation of spontaneous effort, the subjectwill be ventilated at the preset respiratory rate, due to the operationof fuzzy rule 8. Conversely, during the periods of normal effort,support is provided in phase with the subject's efforts. These may beslower than the preset rate (as in FIG. 6) or they may be faster thanthe preset rate.

The subject can acutely increase their spontaneous ventilation at will.Transient increases in ventilation for example due to brief arousalswill lead to a small degree of hypocapnia, but the resultant secondaryreduction or cessation in subject's efforts will again be immediatelymatched by an increase in amplitude A sufficient to hold ventilation ata level of at least 95% of the previous steady level. Conversely,gradual changes in the subject's chemoreceptor set-point over minuteswill result in gradual changes in target ventilation, which will remainat 95% of the subject's actual ventilation. This is shown schematicallyin FIG. 7. The lower tracing shows respiratory airflow graduallydecreasing over a 30 minute period. The calculated recent averageventilation and target ventilation (middle trace) similarly decline overthe thirty minutes. However, since the recent average ventilation isalways larger than the target ventilation, the degree of support alwaysremains at the minimum (top tracing).

An embodiment of the invention was tested in ten patients with severecardiac failure and Cheyne-Stokes breathing during sleep. The targetventilation was initially set to 5-7.5 L/min, and the end expiratorypressure P₀ was set to 8 cmH₂0. The patients were tested on each one ofa control night (no assistance), nasal oxygen at 2 L/min, CPAP (7-10cmH₂O as tolerated, bi-level CPAP (ResMed VPAP-ST™ machine, with VPAP at4 cmH₂0 and IPAP at 12-18 cmH₂0 as required, with the backup rate at 2L/min below the spontaneous rate), and a prototype of the presentapplicant's Auto CS™ machine.

The apnea+hypopnea index (AHI), ASDA microarousal index (ARI), andpercentage of time in slow wave (SWS) and REM sleep were calculatedusing standard procedures. The results are presented as mean.+−.sem. Thestatistical analysis is repeated measures ANOVA after rank transform.

Control Oxygen CPAP VPAP-ST Auto CS AHI (hr⁻¹) 43.3 ± 5⁺   48.8 ± 3.2⁺24.1 ± 3.4⁺  9.0 ± 1.3⁺  4.8 ± 0.9⁺ ARI (hr⁻¹) 48.1 ± 3.6⁺ 34.7 ± 4.5⁺30.8 ± 3.5⁺ 18.4 ± 3.4  15.5 ± 3.2⁺ SWS (%) 13.7 ± 2.8⁺ 19.8 ± 2.6⁺ 19.3± 3.5⁺  20.8 ± 3.05⁺ 21.1 ± 2.7⁺ REM (%) 10.5 ± 2.1⁺ 13.3 ± 2.4⁺ 12.2 ±1.6⁺ 15.3 ± 2.3⁺ 18.4 ± 0.6⁺ *Auto CS P < 0.05, ⁺Auto CS P < 001.

In most subjects, transcutaneous PCO₂ fell by approximately 5-10 mmHgdue to a period of hyperventilation in the first few minutes of awakebreathing. This resulted in some instability of the upper airway andresidual mild Cheyne-Stokes breathing for the first 20-40 minutes ofsleep. Subsequently, Cheyne-Stokes breathing was largely abolished. FIG.4 shows the same subject as FIG. 1, also in stage 3 non-REM sleep, butthis time using the new device. The mask pressure swings are broadlycomparable with those in FIG. 1, but very small changes with time can beseen, as the device opposes any changes in the subject's ventilation. Itis clear that the subject's ribcage movement (ie. measured using athoracic respiratory band) and oxygen saturation (Sa02) are greatlystabilized compared with FIG. 1, and Cheyne-Stokes breathing has beeneliminated.

In some subjects, the period of unstable breathing immediately aftersleep onset could be eliminated by asking the subject to remain awakefor 20 minutes after applying the mask and before going to sleep, inorder to minimize overbreathing immediately prior to sleep onset.

1. A method for treatment of cardiac failure, Cheyne-Stokes breathing orcentral sleep apnea, comprising the steps of: providing a subject withventilatory support; deriving a measure of the subject's instantaneousventilation; and adjusting the degree of ventilatory support to reducechanges in said measure of instantaneous ventilation over a timescalesimilar to that of the waxing-waning cycle of untreated Cheyne-Stokesbreathing or central sleep apnea, while allowing changes in said measureof instantaneous ventilation over a timescale much longer than saidwaxing-waning cycle.
 2. A method for treatment of cardiac failure,Cheyne-Stokes breathing or central sleep apnea, comprising the steps of:providing a subject with ventilatory support; deriving a measure of thesubject's instantaneous ventilation; deriving a measure of the subject'slongterm average ventilation; setting the controlled variable of aservo-controller to a function of said measure of the subject'sinstantaneous ventilation; setting the reference variable of saidservo-controller to a measure of the subject's longterm averageventilation; and adjusting the magnitude of said ventilatory support inaccordance with the output of said servo-controller.
 3. A method fortreatment of cardiac failure, Cheyne-Stokes breathing or central sleepapnea, comprising the steps of: providing a subject with ventilatorysupport; deriving a measure of the subject's instantaneous ventilation;high pass filtering said measure of the subject's instantaneousventilation; and adjusting the degree of said ventilatory supportinversely with said high pass filtered measure of the subject'sinstantaneous ventilation.
 4. A method as claimed in claim 1, wherebythe step of adjusting the degree of ventilator support comprises thesteps of: low pass filtering said measure of instantaneous ventilationto derive a measure of longterm average ventilation; setting a targetsignal equal to a fraction of said measure of longterm-averageventilation; and servo-controlling said measure of instantaneousventilation to at least equal the target ventilation.
 5. A method asclaimed in claim 1, whereby ventilatory support is positive pressureventilatory support.
 6. A method as claimed in claim 5, whereby thedegree of ventilatory support is the difference between a peakinspiratory pressure and an end expiratory pressure.
 7. A method asclaimed in claim 1, whereby deriving a measure of instantaneousventilation comprises at least the steps of: deriving a signalproportional to the subject's respiratory airflow; and rectifying saidsignal.
 8. A method as claimed in claim 1, whereby the degree ofventilatory support provided is clipped to exceed a minimum degree ofsupport, chosen to be less than the degree of support that would performthe subject's entire work of breathing.
 9. A method as claimed in claim1, whereby the degree of ventilatory support provided is clipped to notexceed a maximum degree of support, chosen to be sufficient to performmost or all of the subject's work of breathing, but not sufficient to bedangerous.
 10. A method as claimed in claim 1, including the furthersteps of: the severity of reduction in ventilation is determined; if theseverity of reduction in ventilation is high, then said ventilatorysupport is provided at a preset rate; if the severity of reduction inventilation is zero, then said ventilatory support is provided in phasewith the subject's respiratory airflow; and for intermediate degrees ofseverity of reduction in ventilation, support is provided at anintermediate rate.
 11. A method as claimed in claim 10, whereby theseverity of reduction in ventilation is calculated by comparing thesubject's ventilation with a low pass filtered ventilation. 12.Apparatus for the treatment of cardiac failure, Cheyne-Stokes breathingor central sleep apnea, comprising: a device for providing ventilatorysupport of controllable magnitude; means for deriving a signalindicative of instantaneous ventilation of a subject; and aservo-controller operable to control the degree of ventilatory supportprovided by said ventilatory support device to oppose short-term changesin said measure of instantaneous ventilation, but permit longtermchanges in said measure of instantaneous ventilation.
 13. Apparatus asclaimed in claim 12, wherein the ventilatory support device providespositive pressure ventilatory support.
 14. Apparatus for treatment ofcardiac failure, Cheyne-Stokes breathing or central sleep apnea,comprising: a controllable source of breathable gas at positivepressure; means for delivering said breathable gas at positive pressureto a subject's airway; means for deriving a measure of the subject'sinstantaneous ventilation; and a servo-controller for adjusting thedegree of ventilatory support to reduce changes in said measure ofinstantaneous ventilation over a timescale similar to that of thewaxing-waning cycle of untreated Cheyne-Stokes breathing or centralsleep apnea, while allowing changes in said measure of instantaneousventilation over a timescale much longer than said waxing-waning cycle.15. Apparatus for treatment of cardiac failure, Cheyne-Stokes breathingor central sleep apnea, comprising: a controllable source of breathablegas at positive pressure; means for delivering said breathable gas atpositive pressure to a subject's airway; means for deriving a measure ofthe subject's instantaneous ventilation; means for deriving a measure ofthe subject's longterm average ventilation; means for deriving a targetventilation as a function of said measure of the subject's longtermaverage ventilation; a servo-controller, whose input variable is afunction of said measure of the subject's instantaneous ventilation, andwhose reference variable is said target ventilation; and means foradjusting the magnitude of said ventilatory support according to theoutput of the servo controller.
 16. Apparatus as claimed in claim 12 orclaim 15, wherein said measure of instantaneous ventilation isproportional to the absolute value of the respiratory airflow. 17.Apparatus as claimed in claim 15, wherein said measure of the subject'srecent average ventilation is proportional to the low pass filteredabsolute value of the respiratory airflow, said low pass filter having atime constant of the order of, or longer than the waxing-waning cycle ofuntreated Cheyne-Stokes breathing.
 18. Apparatus for treatment ofcardiac failure, Cheyne-Stokes breathing or central sleep apnea,comprising: a controllable source of breathable gas at positivepressure; means for delivering said breathable gas at positive pressureto a subject's airway; means for deriving a measure of the subject'sinstantaneous ventilation; means for high pass filtering said measure ofthe subject's instantaneous ventilation; and a servo-controller whoseinput variable is a function of said high pass filtered measure of thesubject's instantaneous ventilation, and which adjusts the magnitude ofsaid ventilatory support inversely with said high pass filtered measureof the subject's instantaneous ventilation.
 19. Apparatus as claimed inclaim 18, wherein said high pass filter has a time constant of the orderof or longer than the waxing-waning cycle of untreated Cheyne-Stokesbreathing.
 20. Apparatus as claimed in either one of claim 17 or claim19, wherein said time constant is 100 seconds.
 21. Apparatus as claimedin claim 15, wherein said target ventilation is a chosen fraction of thesubject's recent average ventilation.
 22. Apparatus as claimed in claim15, wherein the servo-control means is operable to servo-control saidmeasure of instantaneous ventilation to at least equal the targetventilation.
 23. Apparatus as claimed in either one of claim 15 or claim22, wherein the servo-control means is operable to increase the degreeof support if said measure of instantaneous ventilation is less thansaid target ventilation, and reduce the degree of support if saidmeasure of instantaneous ventilation is greater than said targetventilation.
 24. Apparatus as claimed in claim 12, wherein theservo-control means is further operable to clip the degree ofventilatory support to exceed a minimum degree of support, chosen to beless than the degree of support that would perform a subject's entirework of breathing.
 25. Apparatus as claimed in claim 12, wherein theservo-control means is operable to modulate said positive said pressurein phase with respiratory air flow where the subject is breathingadequately, and to modulate said positive pressure at a preset ratewhere the subject is not breathing adequately.
 26. Apparatus as claimedin claim 25, wherein the servo-control means is operable to assess theadequacy of breathing by comparing a measure of instantaneousventilation with a target ventilation.
 27. A method for the treatment ofcardiac failure, Cheyne-Stokes breathing or central sleep apnea,comprising the steps of: providing a subject with positive pressureventilatory support, with controllable amplitude and rate; deriving ameasure of the subject's instantaneous ventilation; adjusting saidamplitude of positive pressure by: (a) low pass filtering said measureof instantaneous ventilation to derive a measure of recent averageventilation; (b) setting a target ventilation equal to a fraction ofsaid measure of recent average ventilation; and (c) servo-controllingsaid measure of instantaneous ventilation to at least equal the targetventilation, by adjusting the degree of ventilator support; andcontinuously adjusting said rate by: (a) to the extent that theinstantaneous ventilation equals or exceeds said target ventilation,modulating said positive pressure in phase with respiratory airflow; and(b) to the extent that the instantaneous ventilation is less than saidtarget ventilation, modulating said positive pressure at a preset rate.28. Apparatus for the treatment of cardiac failure, Cheyne-Stokesbreathing or central sleep apnea, comprising: ventilator means forproviding ventilatory support with controllable amplitude and rate;sensor and processing means for deriving a signal indicative ofinstantaneous ventilation of a subject; and servo-control means operableto adjust the amplitude of the pressure support by low pass filteringsaid instantaneous ventilation signal to derive a measure of recentaverage ventilation, setting a target ventilation equal to a fraction ofsaid measure of recent average ventilation and servo-controlling saidmeasure of instantaneous ventilation to at least equal the targetventilation, and further operable to continuously adjust said rate bymodulating said positive pressure in phase with respiratory airflow tothe extent that the instantaneous ventilation equals or exceeds saidtarget ventilation, and modulating said positive pressure at a pre-setrate to the extent that the instantaneous ventilation is less than saidtarget ventilation.
 29. A method for treatment of cardiac failure,Cheyne Stokes breathing or central sleep apnea, comprising the steps of:providing a subject with ventilatory support; deriving a measure ofinstantaneous ventilation; and adjusting the degree of ventilatorysupport to oppose short term changes in said measure of instantaneousventilation, but permitting longterm changes in said measure ofinstantaneous ventilation.